Revolution Medicines, Inc.

Today, ladies and gentlemen, and welcome to the Revolution Medicine Second Quarter Fiscal Year 2021 Financial Results Conference Call and Webcast. At this time, all participants are on a listen-only mode. Following management's prepared remarks, we will have a question and answer session. To ask a question at that time, please press star followed by the one on your touchtone telephone. Please be advised that today's conference call is being recorded. If anyone has difficulty hearing the conference, please press star zero for operator assistance. I would now like to hand the conference over to Peg Horn, Revolution's Chief Operating Officer, for opening remarks. Peg, you may begin.

Good afternoon, everyone, and thank you all for joining us today. Joining me on today's call are Dr. Mark Goldsmith, Revolution's Chairman and Chief Executive Officer, Dr. Steve Kelsey, the company's President, Research and Development, and Jack Anders, our Senior Vice President of Finance and Principal Accounting Officer. As we begin, I'd like to caution you that our presentation today will contain forward-looking statements within the meaning of the Private Securities Litigation Reform Act regarding the current beliefs of the company with respect to our business. These statements are subject to a number of assumptions, risks, and uncertainties. Actual results may differ materially from these statements, and except as required by law, the company undertakes no obligation to revise or update any forward-looking statements. I encourage you to review the legal disclaimer slide we are presenting today, as well as all of the company's filings with the SEC concerning these other matters. During this presentation, we will be referring to a few slides from our corporate presentation. The entire presentation was posted to our website immediately prior to this call. With that, I will turn the call over to Dr. Mark Goldsmith, Revolutions Chairman and Chief Executive Officer. Mark.

Thank you and good afternoon. Welcome to our Q2 earnings call. This is Revolution Medicine's first earnings call and we look forward to having this opportunity to connect with our investors on a regular basis. After our prepared remarks today, we will host a Q&A session. Treatment for RAS-addicted cancers reached an important milestone in Q2. with the first FDA approval of a targeted medicine for lung cancer carrying the KRAS G12C mutation, Amgen's Lumicras, or Sotiracib. Likewise, R&D at Revolution Medicines continued making excellent progress, reinforcing our belief that the company's innovative and cohesive asset portfolio can drive rational, mechanism-based, and beneficial combination treatments for patients with RAS-addicted cancers. Our ambition is to serve remaining and significant unmet needs for patients with KRAS G12C positive tumors and even larger opportunities to benefit those with cancers driven by other non-G12C RAS variants, as shown on slide four. Today, we will highlight important progress we've made on our exciting tricomplex RAS-on inhibitors that extends the momentum we've described previously. We will also provide an update on several aspects of RMC-4630, an advanced and important asset in our RAS companion inhibitor portfolio. We will report on two combination drug strategies that have been under evaluation in the RMC-4630-02 study. The so-called clamping approach with our SHP2 inhibitor RMC-4630 in combination with the MEK inhibitor, cobimetinib, directed against advanced RAS-addicted cancers lacking a targeted RAS inhibitor. and a second approach with RMC4630 combined with the EGF receptor inhibitor Osimeritinib aiming to enhance clinical benefit in EGF receptor mutant lung cancer. We will also explain our continued commitment to treatment strategies combining a direct RAS inhibitor with RMC4630 and we'll announce an exciting high priority combination study sponsored by Revolution Medicines evaluating RMC4630 in combination with Sotiracib in KRAS G12C-positive lung cancer under a new clinical trial collaboration and supply agreement with Amgen that builds on and is a complement to the CodeBreak 101 trial exploring this combination across multiple cancer types. The RMC4630-03 study is designed to allow us to better define patients who may most benefit from the combination of our SHIP2 inhibitor with the KRAS G12C inhibitor through analysis of cohorts with and without certain commutations. Steve Kelsey, Revolution's President of R&D, will provide more information on the new O3 study and our other clinical programs after I provide an update on our RAS-on inhibitors. For KRAS G12C positive lung cancer and colorectal cancer in particular, we continue to believe there's an opportunity to increase clinical response rates and or durability as suggested by this table on slide five, summarizing some key outcomes reported with first generation KRAS G12C off inhibitors so far that show both the clinical benefit of targeted drug and areas of ongoing opportunities. With these unmet needs in mind, we are pursuing development of several new RAS on inhibitors. A key element of the strategy for our KRAS G12C on inhibitor is consistent with the successful generational paradigm established previously with advanced generation targeted inhibitors for tumors with EGF receptor mutations. In Q1 of 2021, we had introduced the compelling profile of the development candidate RMC6291, our first-in-class potent oral and selective tricomplex inhibitor for KRAS-G12C, as summarized on slide 10. Expanding from earlier examples shown previously, in Q2, we reported additional examples of deeper, more uniform, and or more sustained anti-tumor effects in xenograft KRAS-G12C cancer models compared to a first-generation RAS-OF inhibitor. These experiments are part of a growing body of evidence that RMC69-1 has best-in-class potential among KRAS-G12C inhibitors. Also in Q2, various newly emergent RAS or RAS pathway mutations were reported in 39% of patients exhibiting resistance to treatment with Atagracib. And the described mutations provide a critical roadmap for treatment approaches to combat these mechanisms of clinical failure. As shown in this table on slide 14, the company has expanded on initial results published in Cancer Discovery by Dr. Ryan Corcoran's team at the Massachusetts General Hospital and Harvard Medical School by demonstrating that RMC6291 is active against all second site resistance mutations reported thus far from patients treated with adagracib. As many of these mutations also confer resistance to sotiracib and other KRAS-G12C-Auth inhibitors, the activity of RMC6291 in this setting illustrates a distinguishing property of the molecule that may be useful for preventing or treating emergence of these resistance mutations. RMC-6291 continues on track in its IND-enabling development program toward its expected IND filing in the first half of 2020-22. We also showed additional progress in addressing non-G12C oncogenic RAS variants, which account for approximately 85% of all incident RAS-addicted cancers and for which no targeted treatments are available. Earlier in 2021, we had described the compelling profile of our second development candidate, RMC6236, a first-in-class potent oral and RAS-selective tricomplex inhibitor for multiple variants of RAS, as summarized on slide 17. Expanding from earlier examples of KRAS G12V and KRAS G12D cancer models shown previously, in Q2, we described additional preclinical data in a growing body of evidence that RMC6236 has first-in-class and best-in-class potential for treating KRAS G12V and or KRAS G12D tumors across multiple histotypes. Among the multiple resistance mechanisms, resistance mutations in adagrassive treated patients that were reported in Q2, a notable group of emergent RAS variants was described that are expected to be insensitive to KRAS G12C off inhibitors and to RMC6291. As shown on slide 22, These mutations include new substitutions at KRAS G12 in the upper panel, KRAS G13 in the lower panel, and NRAS Q61 also in the lower right panel. Importantly, we've now shown in preclinical experiments that RMC6236 is active against all of these clinically observed variants, as well as a broader panel of KRAS G12 mutants that to date haven't been described in patients. Hence, these findings indicate that RMC6236 has important properties that may be useful for preventing or treating emergence of these RAS oncogene switch resistance mutations. In Q2, we also reported information about the potential for additive benefit in combinations of either RMC6291 or RMC6236 with a checkpoint inhibitor. For example, as shown on the left of slide 26, in immunocompetent mice engrafted with the syngeneic Ras mutant tumor, RMC6236 induced a favorable transformation of the tumor immune microenvironment characterized by an increase in infiltrating CD8 T cells and a decrease in immune-suppressive M2 macrophages. As shown on the right, RMC6236 alone was quite active against growth of these syngeneic tumor grafts, including inducing a number of complete responses. and anti-PD-1 antibody alone was active as well, but the two together led to complete responses in all animals. These results are encouraging about the potential clinical benefit of combining our RAS-on inhibitors with PD-1 inhibitors in treating anti-PD-1 sensitive tumors. Like RMC6291, RMC6236 continues on track in IND-enabling development, and we continue making very good progress. on advancing additional mutant selective Ras-on inhibitors. Our corporate goal is to select a third development candidate this year to advance into IMD-enabling development and others subsequently. Today, we'd like to show you some new evidence of our drug discovery capabilities by focusing briefly on two programs we disclosed in late lead optimization, KRAS G13C and KRAS G12D. Shown on the left of slide 29, is a graphical surface representation of the SW1-2 region of the Ras-on protein, which shows that amino acids 12, highlighted in blue, and 13, highlighted in red, lie adjacent to each other in the protein, and both are very close to the Ras-on inhibitor binding site, highlighted in dark pink. Our previous work enabled RMC6291 to selectively engage the oncogenic cysteine at position 12 in the mutant KRAS-G12C-on protein, as indicated by the upward shift of the KRAS G12C protein band in the cross-linking experiment on the left. We have now been able to engineer new RAS-on inhibitor compounds that covalently engage the specific oncogenic cysteine at position 13 in the mutant KRAS G13C-on protein, as indicated by the upward shift of the KRAS G13C protein in the middle panel. Further, the exquisite molecular control we bring to the design of these remarkable compounds enable selective covalent binding to the cysteine-13 variant by one compound without detectable binding to the cysteine-12 variant, or conversely, selective covalent binding to the cysteine-12 variant by another compound without covalent binding to the cysteine-13 variant, despite the similar positions of the cysteines at positions 12, and 13 in these RAS variants. Thus, the covalent warheads in these compounds are tuned to work only when positioned precisely and optimally with the free-file group of the particular cysteine residue for which they are designed, a degree of on-target selectivity that is very encouraging. We also report today that we have extended covalent chemistry beyond cysteines to the oncogenic aspartic acid in the KRAS G12D on variant, an exciting innovation and major achievement. Shown on the right of slide 29 is a representative compound that binds and cross-links to the KRAS G12D on variant, as indicated by the upward shift of the KRAS G12D protein. Important evidence of the selectivity of this engagement is the absence of significant cross-linking to its close cousin, the KRAS G13D variant, despite the close proximity of aspartate 12 and aspartame 13 to one another. We're very proud of both of these quite differentiated chemical series that enable potent and highly mutant-selective inhibition of oncogenic RAS signaling. Indeed, as shown here, each of these compounds shows impressive tumor cell growth inhibition in the corresponding genetic context, as anticipated by the specific cross-linking pattern shown above. These laboratory-based feeds offer further insight into the groundbreaking drug design and execution capabilities deployed as we continue expanding our portfolio of RAS on inhibitor assets, and we look forward to providing further updates as these programs reach further milestones. We'd also like to provide an update on the good progress within our RAS companion inhibitor pipeline. Previously, we identified combinations with RAS inhibitors as a core strategic element of our SHIP2 inhibitor program, and we remain optimistic about this strategy. To illustrate this concept, we recently shared data on this example of a drug-resistant KRAS G12C colorectal tumor xenograft in slide 32. In contrast to another colorectal cancer model we showed previously that is highly sensitive to single-agent RMC6291, This particular colorectal cancer model exhibits only a modest growth inhibition response to RMC6291 monotherapy in the blue line, which we believe relates to the role of wild type or normal RAS proteins in supporting growth of these tumors. Notably, combining our shift to inhibitor RMC4550, a tool compound we often use for preclinical research, with RMC6291 induced deep and sustained regressions in the tumor xenografts as shown on slide 32. Hence, while RMC6291 itself has a superior preclinical profile to first generation KRAS G12C inhibitors as measured in a variety of models we've shown previously, additional anti-tumor impact can be obtained by the additive contribution of our SHIP2 inhibitor. We believe that combining such agents in the clinic will prove to be a compelling therapeutic strategy And now I'll turn things over to Dr. Steve Kelsey, our president of R&D, to bring you up to date on these efforts. Thank you, Mark.

In monotherapy clinical studies to date, RMC4630, our clinical stage SHIP2 inhibitor, compares favorably with competitors and is well set up for continued evaluation of potential combination benefits with RAS inhibitors. Notable features of our RNC4630 program include the use of an innovative intermittent dosing schedule to optimize for activity and tolerability, an absence of cardiac and liver dose limiting toxicities in the dose escalation work, a focus on patients with RAS mutant tumors, observed clinical activity with best responses, including partial response and the complete response, observed reduction in driver oncogene frequency detected in circulating tumor DNA samples, and evidence of favorable modulation of the tumor immune microenvironment in tumor samples from treated patients. In Q2 of the annual ASCO meeting, another prominent SHP2 inhibitor program, TNO155 by Novartis, presented its first monotherapy clinical data that showed a different clinical strategy and dosing paradigm with less encouraging output so far. We continue to believe that RMC4630 has the potential to be a class leading SHP2 inhibitor and thereby a class leading RAS companion inhibitor. The earliest combination studies we were able to begin before RAS inhibitors were available for clinical testing were combinations with inhibitors of two other targets in the RAS signaling pathway, MEK and EGFR. And today, we provide an update on both. In the absence of direct inhibitors for most RAS mutants, our first approach was to try to clamp the RAS pathway by combining our inhibitor of SHP2, RMC4630, which suppresses the top of the signaling cascade or upstream of RAS, with covimetinib, a MEK inhibitor, which suppresses the bottom of the signaling cascade or downstream of RAS. Preclinical work from several groups, including ourselves, had suggested modest but undoubtedly combinatorial antitumor potential for this approach. which we felt merited clinical evaluation in the context of serious unmet needs. In the RNC-4630-02 study, a group of patients with Rasbutin non-small cell lung cancer were treated with the RNC-4630 plus COVID method combination, using the recommended phase two dose and schedule that we have described last fall. 11 subjects were available for efficacy, we observed acceptable tolerability and one patient with a KRAS G12V tumor mutation and gene amplification of that mutation exhibited a confirmed partial response with an almost 45% tumor volume reduction. In a group of patients with RAS mutant colorectal cancer, we had 25 efficacy-evaluable subjects. Here, too, we observed acceptable tolerability, but the best clinical response was stable disease. Together, these results are encouraging in that they further support the anti-tumor activity of RMC4630 in a way that can deliver clinical benefit in RAS-driven cancers and can be combined tolerably with other drugs. However, the combination also showed insufficient clinical benefit to justify advancing this approach. To us, it strongly points us back to the primary hypothesis for RAS-addicted cancers, which is to focus our efforts on using RMC4630 as a companion for direct RAS inhibitors. Our second and quite different approach was to try to enhance the clinical benefit of a best-in-class receptor tyrosine kinase inhibitor, ozimertinib, by including RMC4630 to suppress adaptive resistance mechanisms that may eventually reduce the efficacy of the EGFR inhibitor upon long-term treatment. Preclinical work had supported the antitumor potential for this approach. which we felt merited clinical evaluation. We had previously communicated that we were not confident these two agents with well-recognized on-pathway side effects could be combined clinically, a precedent set by the combination of ozumertinib with the MEK inhibitors. And indeed, last quarter, we reported intolerability at the early dose levels in the RMC463002 study. In fact, we did not identify a combination dosing schedule with acceptable tolerability, even employing our intermittent dosing paradigm for RMC4630, indicating that the combined on-target toxicity caused by suppression of RAF signaling in normal tissues caused by these two agents together presents too big a hurdle to justify advancing this approach. Again, this outcome reiterates our prime combination hypothesis for treating RAS-addicted cancers, which is combining IMC-4630 or other RAS companion inhibitors with direct RAS inhibitors. And that strategy will be our highest priority going forwards. In view of the response rates, emerging drug resistance profiles and resistance mechanisms for the leading KRAS G12C off inhibitors, we continue to have conviction about combining RMC4630 with direct RAS inhibitors. Since, to our understanding, all clinical toxicities driving our selection of the recommended phase two dose of RMC4630 have been attributable to RAS pathway effects in normal tissues, We have no reason to believe that combining RMC4630 with a RAS mutant selective inhibitor would be compromised by additive dose-limiting toxicities. Amgen continues to enroll the COVID-19 Break 101 Subpart C study of sartoracid with RMC4630 in advanced non-small cell lung cancer, colorectal cancer, and other solid tumors. As noted earlier in the quarter, the dose escalation work continues, evaluating RMC4630 at the target dose of 200 milligrams daily on a day one, day two weekly schedule. The full dose used by us in monotherapy in combination with cetirisib at 960 milligrams daily. A combination dose for expansion is expected to be achieved by Amgen in the second half of this year. We are encouraged by this work and it continues to be a productive clinical exploration of the combination strategy. RedMed is also excited to announce today an expansion of our collaboration on this drug combination with Amgen with the RMC4630-03 study. I will provide a more detailed update on this study momentarily. In addition, We plan to combine IMC4630 with RMC6291, our KRAS G12C on inhibitor, and potentially other compounds from our RAS on inhibitor collection as these become available. Finally, the TCD16210 study sponsored by Sanofi continues, evaluating IMC4630 plus pembrolizumab. We are pleased to report today the combination will now be evaluated in an expansion cohort of patients with previously untreated advanced PD-L1 positive non-small cell lung cancer. This study could provide the foundation for a future clinical evaluation of the triplet of a RAS inhibitor, RNC4630, and a PD-1 inhibitor. Regarding the new RNC4630-03 study, Informed by preclinical data, the CodeBreak 101c worked to date and important learnings in the field over the last few years since the CodeBreak protocol was written. The RMC4630-03 study was designed as a global phase two study of the combination of satoracib plus RMC4630 in advanced KRAS-GTLC non-small cell lung cancer that have not previously received a KRAS-GTL-C inhibitor. It is intended to establish the extent and nature of additional clinical benefit from combining these two agents and to inform the design of a possible registrational trial. While the O3 study is complementary to COBREAT-101C, it has several important differences. The RMC46303 study will enroll approximately 46 non-small cell lung cancer subjects with two cohorts that are defined by commutations that may affect the outcome to either KRAS inhibitor or SHIP2 inhibition. First cohort will have KRAS G12C positive tumors without commutations, and the second cohort will have KRAS G12C positive tumors with commutations, such as KEEP1, or STK11 mutations. This will allow us to better define who may most benefit from this promising combination strategy. Unlike COBREAT-101, the study will restrict eligibility to second and third line therapy, and it will enroll outside the United States as well as within the United States. WebMed is sponsoring and executing this study under its global partnership with Sanofi. with clinical supply of sotiracib provided by Amgen for the ex-US sites where the drug is not yet approved, which is expected to be a major source of enrollment now that sotiracib has been approved in the United States. For data analysis and full interpretation, we will have the ability to draw from both COBRE 101C results and the O3 study results. We review RMC463003 as an important and exciting clinical study. We are preparing to launch the study and we expect the first patients to be enrolled in the second half of this year and to have preliminary findings by the end of 2022. Back to you, Mike.

Thank you, Steve. Today we highlighted recent progress regarding several important assets in our strategic development stage pipeline, addressing key drivers of RAS addiction and drug resistance, and provided further visibility into the remarkable drug discovery advances within our Rason inhibitor program that will help power advancing additional research stage assets into development. In addition, our mTORC1 selective inhibitor, RMC5552, continues advancing in monotherapy dose escalation, and our SOS1 selective inhibitor, RMC5845, is on track to be IND ready by the end of this year. Slide 41 outlines our corporate milestones. I'd like to highlight several of these in particular. In our RAS-on inhibitor pipeline, we continue to anticipate IND filings for both RMC-6291 and RMC-6236 in the first half of 2022 and selection of a third RAS-on inhibitor development candidate later this year. For RMC-4630, later this year, we anticipate selection by Amgen of a dose for further study with Sotiracib in Code Break 101, and to begin dosing patients in our new O3 study with Sotiracib. I'll now turn things over to Jack Anders to review our financial results. Jack?

Thank you, Mark, and good afternoon, everyone. We ended the quarter with $646 million in cash, cash equivalents, and investments. Revenue for the second quarter of 2021 was 8.7 million and consists entirely of revenue under our collaboration agreement with Sanofi. Total operating expenses for the second quarter of 2021 increased to 53.2 million, largely driven by R&D expenses, which were 45.9 million during the quarter. Net loss for the second quarter of 2021 was $44.3 million, or $0.60 per share. Turning to financial guidance, we continue to expect full-year GAAP net loss to be between $170 and $190 million, which includes estimated non-cash stock-based compensation expense of approximately $20 million. Our GAAP net loss for the first half of 2021 was $81 million, and we expect net loss to increase during the second half of the year, primarily driven by increases in operating expenses as we advance our preclinical and clinical programs. And with that, I'll now turn the call back over to Mark.

Thank you, Jack. We believe that RevMed is in an excellent position to continue aggressively pursuing our mission on behalf of cancer patients. We have a compelling strategy, a growing set of exciting product assets, and a strong balance sheet. We're proud of the tireless commitment to patients by our organization and are grateful to the patients and their families and the many partners who work with us for providing RevMed with the opportunity to advance our unique pipeline of Ras-on inhibitors and Ras-companion inhibitors which we believe may transform the treatment of RAS-addicted cancers in the future. This concludes our prepared remarks for today, and I'll now turn the call over to the operator for the Q&A session. Operator?

Thank you. As a reminder to ask the question, please press the star key followed by 1 on your touchtone telephone. To withdraw your question, press the pound key. Again, that's star 1 to ask the question. Please stand by while we compile the Q&A roster. Our first question comes from the line of Chris Chibutaini with Goldman Sachs. Your line is open.

Chris Chibutaini Yes, hi. Thanks very much for the questions. Want to get a sense for timelines for clinical data. A lot of progress and updates with your clinical planning here, obviously. With the study that you have with the TORA-SEB, this O3 study, it looks as if we're going to get the preliminary findings in the second half of next year, 2022. Can you help put that timeline in context with your confidence in starting the Phase 2 now? And also, will we be able to get a sense for what Phase 1 data looks like?

Yeah, thanks Chris. I'll try to identify, I'll try to answer your questions in a logical sequence if I can. Firstly, the O3 study to which we refer is complementary to the Amgen-CoV-1C study. The data, the totality of the data will be evaluated together and we expect, as we said, the first run-up to be towards the end of next year. The Phase 1 data to which you alluded, there is going to be a very brief safety run-in for the O3 study. We are compelled to do that. because a recommended phase two dosage schedule has not yet been defined that we can legitimately and ethically start the ATRI study with. And obviously, we will be able to use that for the expansion of the ATRI study. What we cannot do is comment on when Andrew will release data from the phase one components of the COBRA other than we are guiding to the fact that they will select the dose in the second half of this year. What we can't tell you is when they will disclose that.

Okay, that's helpful. With the studies that have been discontinued with the Amgen program, Can you provide us with a preliminary sense for what impact you feel the design of the studies may have factored into this outcome in the decision?

Just to clarify, you're talking about the Covimetinib and Oxymeritinib studies, the O2 studies?

Yes, that's correct, yeah.

I'm not sure. Steve, do you want to comment on that? I'm not sure what design of the studies, what aspect of design you were referring to was really the choice of drugs that we're combining with there, but maybe Steve can clarify.

Yeah, I think there's two components to the question. One is what decision are we making and why are we making it? And then the second is how the design of both the COBE method combination and the ultimate combination didn't see as encouraging efficacy as we want to see moving forward. So let's be clear about the reasons why we're not moving forward with those two combinations. The first and most compelling one is that the efficacy profile wasn't sufficiently compelling to justify moving forward, but there is also a large component of prioritization here as well. We have been but very publicly moving towards combining the companion inhibitors that we have, which include RMC4630, with RAS-directed therapies that we and others are making. And that's an important part of our consideration here. It's really about where do we think the best place to go for RAS-addicted cancers and patients with RAS-addicted cancers is, as much as it is the data per se from the states. I don't think there was any design fault with the studies. We think we have comprehensively tested the hypothesis, at least as far as we can, with a mechanism to code the mechanism. And the data is fairly, in our opinion, is conclusive in that respect. And as you are aware, we We are still supporting the Netherlands Cancer Institute to do a study in combination with in pancreatic and colon cancer. And in as much as that represents a slight variation on the hypothesis, then we'll be interested to see the outcome from that experiment. But I think we designed the best experiment we could. And we are making the decision we made for compelling reasons, both strategically and .

And maybe if I could just add to that, Chris, just to see if I can get at the question that you're raising here. I think it goes back to the indirect strategy of the clamping approach, which is one that we now disfavor. And that is trying not actually inhibiting the cancer driver, but inhibiting the pathway upstream and downstream. And that appears to deliver some benefit. There's modest benefit. We did see a PR and a KRSG-CoV positive patient. But it's just not sufficient in our view to justify pursuing. And furthermore, we have direct inhibitors of many different variants of RAS coming forward very shortly, as you know. And so that makes much more sense to us is to combine them, to combine a direct RAS inhibitor with the RAS companion inhibitor. And after all, we call the RAS companion inhibitors RAS companion inhibitors to indicate that they'll be combined with RAS inhibitors. So I think that all makes sense. But maybe that's the design feature you're asking about. The hypothesis seemed reasonable. There was clinical data to support it. And there's a serious unmet need that couldn't be satisfied by any existing compound, so we tested it. But we don't think it will be those results are dispositive or read-through to a strategy that involves a direct inhibitor plus a RAS companion inhibitor. I think that's really the key point maybe that you're getting to.

Yeah, I appreciate the thoughtful responses, and we'll certainly look forward to your continued progress on the Holyone-Rasson programs. Thank you.

Thanks, Chris.

Thank you. Our next question comes from the line of Mark Frane with Cowan. Your line is open.

Hi. Thanks for taking my questions. Maybe just to start on the O3 trial, with the brief safety run-in that you discussed, is all of it going to be run at 200 milligrams day one, day two, or are you going to have some dose exploration built into that run-in? And then related on that trial, why is the right structure to move now with a RevMed sponsored trial rather than, you know, waiting for the formal selection of a recommended phase two dose within code break and kind of keeping everything contained within that first collaboration with Amgen.

Yeah, thanks, Mark. Appreciate those questions. I think I'm going to comment on the second question and then Steve can take a crack at the first one and you can add to the second one if he wants, which is why I do it now. I think it's important to emphasize patients as opposed to the exploratory ongoing Code Break 101C study. And we feel there's sufficient information now to really go after that. There is some overlap with Code Break 101C, but this is a more advanced design. It builds on things that we've learned over the last couple of years that we didn't know when the Code Break study was designed. And we think it's also urgent to get to the answers to the questions. And the question that we're posing here has to do So we think it makes sense to move forward, and there will be just a little bit of overlapping time there, but it will give us the advantage of getting to the answer as robustly as possible and as quickly as possible with regard to lung cancer. Steve, you can comment on that, you can comment on the first question, whatever you'd like. Okay, you answered the second part of the question.

I'm going to ask Paul a question. We'll have you address it. With regards to the, you know, the dose expiration at the beginning, it's not really a dose expiration. I mean, we basically have two choices, 140 milligrams day one, day two, or 200 milligrams day one, day two. We're currently, you know, as we said, we know, and I think we've publicly disclosed where Amgen are in COVID-101C with regard to doses, RMC-463O in combination with their full doses of sotiracin. So, We fully expect to move forward with the Phase II component of this study at what we call the target dose of RMC463, which is 200 milligrams, day one, day two, with the current timing and just the way that COVID-191C study is at the moment. We're obliged to build a short safety budget into our study. So it's more of an operational detail, but it is a real sort of dense exploration. And, you know, if I'm wrong, then we'll go back and revisit it. But I would be surprised if we don't end up using it on target those

Okay, thanks. That's very helpful. And then maybe a bigger picture question, just given the kind of totality of the updates today, what have you kind of learned about the level of wild-type RAS inhibition that's acceptable and kind of how that makes you think about designing your multi-RAS inhibitors on and kind of how much spillover effect either – the multi-RAS or the targeted ones are allowed to have before they're acceptable profiles to move in when you ultimately want to use them in combinations.

Thanks, Mark. Let me just add something to that previous discussion about timing. It just also occurs to me that this is important to mention. Amgen is collaborating with us on this O3 study. They view it as an extension of, expansion of, complement to the current Code Break 101C study, just as we do, as does Sanofi. So we have three companies all getting together, agreeing on that concept. And based on that, there's no reason not to proceed with it. And as Steve said, we're so close to finalization of those that there's no reason to wait. Now, with regard to what have we learned, again, maybe I'll just take a crack at this, which is we already knew that SHIT2 inhibition has a tolerability constraint because of its effect in normal tissues. There's nothing selective about its action in tumor cells, as you know. We designed the intermittent dosing regimen, which we still have a lot of confidence in, as a way to take advantage of tumor cells being able to tip into apoptosis if they're covered deeply enough and long enough, but they don't require continuous coverage. And so we're trying to create a pharmacologic way of manipulating tumor cells versus normal cells. But there's a limit to that. And the limit to that is probably 200 milligrams to do one day two, you know, or thereabouts in a dosing regimen. And we have seen objective responses with that sort of regimen. So it's clearly a very active agent with our competition. We're also having to take into account the landscape, and when there are G12C specific, you know, mutant specific inhibitors that are in play, as LumaCrafts has now approved, and there will be others coming, we have to make sure that what we're doing is additive in terms of clinical benefit, and not sub what you can achieve with those targeted mutant selective agents. And so, I think we're still, net of all that is we're still and when dosed in the ways that we dose it, and we fully expect that it will show additivity, but that's why we have to do the clinical studies when we combine the thoracic inhibitors. With regard to read-through to RMC6291, which is the G12C selective inhibitor, I don't think there's any read-through whatsoever that we're aware of to a mutant selective inhibitor like G12C, multi-RAS inhibitor, I think you're right in principle to raise that question. I think we had already learned what we needed to learn before. I don't think this changes, that anything was changed by the results that we just described. That is, that there is a limit to how much you can dose back, how continuously you can inhibit all RAS targets, that's for sure. But we also know that RAS-addicted tumors are particularly sensitive to inhibition of the RAS driver and that it is possible to achieve quite deep anti-tumor effects. And we show this, as you know, across multiple preclinical models that we never achieve with a SHIP2 inhibitor alone or a SHIP2 inhibitor even when combined with a MEK inhibitor. So I think the tolerability limits are there, but in the right context. And when combined specifically with inhibiting the mutant driver, even if it's not a mutant-selective inhibitor, one can achieve quite profound effects. And as you know, there's precedent for that with Terceva, EGF receptor antagonists, and so on that have had profound impacts in tumors at tolerable levels. So I think we feel very good about RMC6236. We continue to evaluate it, but everything continues going in the same direction. We feel terrific about RMC6291. And then the combination strategy of combining a companion inhibitor with the RAS inhibitor is on the forefront of our thinking. And so the O3 study, I think, is the first example where we really get to deploy that fully as we prepare to bring forward the rest of the RAS inhibitor pipeline.

Okay. Thanks for that. Very helpful.

Thank you. Our next question comes from the line of Michael Schmidt with Guggenheim. Your line is open.

Hey, guys. Thanks for taking my questions. I had one regarding the Keytruda combination with RMC4630. I guess nice to see that you're moving forward here with a Phase II. You know, first question is, was it driven predominantly by safety and you know, mechanistic, rational, or also by clinical efficacy data. And then perhaps if you could speak to a decision to move into PD-L1 positive patients in this initial Phase II study and how you should think about a potential, you know, longer-term registration path for this combination.

Thanks, Michael. Let me just give a quick preview. dose escalation work that Sanofi did. They're the sponsor of that study, so when they decide to disclose it, they will. So we can't really address your carefully worded question about was it tolerability or efficacy that drove it, but it was primarily intended as a safety and dose escalation study. That was the purpose of it. But what's now going to be tested is, as you point out, in PD-L1 positive lung cancer and particularly first-line treatment, so previously untreated patients, which is an exciting move and maybe Steve can speak to that. Sure.

I think it helps to explain where we think we may end up in the event of a positive study because I think that will explain the rationale behind the study in the first place. There, if it turns out that adding the SHIP2 inhibitor to Pembrolizumab in the context of PD-L1 positive non-small cell lung cancer, which, by the way, does include Rasputin non-small cell lung cancer, then we really, it leaves us with two large opportunities. One is obviously that There are a very limited number of drugs that improve outcomes over and above checkpoint inhibitors alone, without significantly increasing the toxicity. And obviously, if a shift to inhibitor can do that, then that presents a huge opportunity, not just in lung cancer. There are a lot of other tumors where pedigree is like another PD1 or PA1 inhibitors that are used. The second, and probably from our perspective, the primary driver when we set about doing this is the fact that checkpoint inhibitors are currently standard of care for RAS mutant lung cancer. And we do foresee a future state where the double chemotherapy for RAS mutant lung cancer is replaced by the combination of a RAS-directed inhibitor, whether it's a G2C inhibitor or one of our other RAS inhibitors for other RAS mutations. in combination with a companion inhibitor like RNC4630 and then plus Pembrolizumab. Now that requires us to demonstrate that each component, each dominant component of that triplet is tolerable. And that's the primary intent of that study, which, you know, we have declared a recommended phase two dose and scheduled moving into the phase two expansion of that study. Unfortunately, I won't tell you what it is at the moment. eventually you will learn and then it will become clear what the tolerability profile looks like. All we can say at the moment is the tolerability profile is perfectly acceptable and encouraging enough for us to want to move forward into the phase two efficacy testing. There is a very mechanistic basis for doing it as well. Again, going right back to the very beginning, in fact, a paper published by and Genentech back in 2017 showed very clearly that one of the roles of SHIP2 was to regulate checkpoint signaling. And so there's a huge rationale for a SHIP2 inhibitor augmenting the effects of checkpoint inhibition. We have also subsequently demonstrated both in prefrontal models and in patients that SHIP2 inhibition activate both the innate and adaptive immune system in a way which should be beneficial. I mean, an anti-tumor eclectic should be helpful rather than a hindrance. And so when you compound the mechanistic basis of SHIP2 inhibition as demonstrated in the PD studies from our clinical trials, The fact that checkpoint inhibits is our standard of care for RAS mutant lung cancer and the opportunity beyond RAS mutant lung cancer, I think it's a very compelling place for us to do a study.

Got it, okay. And then on, just wanted to get your thoughts on Amgen's recent decision to also study Sotirasa with The word is SHIP2 inhibitor, actually. Just curious if you have any thoughts on that and perhaps conversely have plans to evaluate 4630 with Mirati's KRAS inhibitor.

Yeah. I think for us, the main thing it suggests is that Amgen continues to have a high interest in SHIP2 as a target and using it as a co-target along with the mutant driver or perhaps mutant driver. So I think that's a very positive signal. As to why they chose specifically TN-0155 or something else, I couldn't speak to that at all. You know, it obviously is a leading SHP2 inhibitor. So, you know, it may be as simple as that. You know, what they've indicated publicly, I'll just reiterate sort of my interpretation of David Reese's comments, which are that they think it's an important target, They want to make sure that the LumaCrafts franchise, which is rapidly building, has access to whatever makes it to the finish line, but that they have no particular concerns about RMC4630 and continue to support Code Break 101C and are excited about it. And what he couldn't say then, but now you can read into it, is that they're also excited about the DO3 study that, of course, they knew we were about to announce, but he couldn't speak to that then. I don't think it reads at all negatively on RMC4630. If anything, it reads positively on it. And we've always suggested that everybody would dance with everybody else when it comes to these sorts of companion inhibitors. You know, until the music's over, until we know all the answers, there's a dance to be danced. And so people are going to switch around and try different partners and We've been doing that. We'll continue doing that, and I suspect everybody will do that. That makes perfect sense in a rational approach to drug development.

Yeah, that makes a lot of sense to me. Well, thanks for your comments there, Mark, and thanks for taking my question. Thank you.

Thank you. Our next question comes from the line of Jonathan Chang with SVB Liebrink. Your line is open.

Hi, guys. This is for Jonathan Chang. Thanks for taking my question. For RMC5845, the SOS1, just a clarification, is this an asset that would be considered for, like, a potential out-licensing, or is this simply a delay in a potential IND filing? And then I guess a related question, are there any features of the molecule itself that kind of played into the decision, or was it just the other priorities? Thank you.

Yeah, thanks for your question. I don't think that there are specific features of the molecule that are affecting that decision. I think it's primarily a prioritization decision. You know, we're moving two compounds into the clinic next year. We already have two compounds in the clinic. We said that there's at least another one coming and several more behind that. So, you know, over the next 12 months, we've got our hands quite full. And RMC 6291 is entering a crowded space, and RMC 6236 is entering a very large space. So those are pretty big programs. And we just announced the O3 program, which is going to be a significant commitment of resources. So I think it's really more a timing question. And we will evaluate. We'll continue evaluating what's the right timing for moving that forward. licensing. I'm not sure why we would do that since we have an integrated approach to RAS-driven tumors, and having a good quality SOS1 inhibitor is part of that approach. It's not on the point of the sphere, but it's part of our overall integrated approach.

Got it. Thank you for taking the question. Thank you.

Thank you. Our final question comes from the line of Eric Joseph with JP Morgan. Your line is open.

Hi, good evening. Thanks for taking the question. Just to follow up on the O3 study, I'm curious to get maybe a bit of a sense of the strategic rationale to pursue lung cancer as opposed to perhaps colorectal, given the sort of the relatively higher unmet need and the lack of objective responses there. I guess, was this decision based on anything that you've seen thus far in code break 101 and is combination potential in colorectal cancer is something that might still be on the table.

Thanks for your question. I think Steve's got some comments to make on that.

Yeah, let's start with the colon cancer bit first. Absolutely, it's on the table. The reason for focusing on non-small cell lung cancer, I think, is is really twofold. One is we were swayed to some extent by the data that was presented at AACR and then published in the Union Journal of Medicine about mechanisms by which tumors escape from KRAS G12C off inhibitors. I think if you look at that data, the potential for a SHIP2 inhibitor to intervene meaningfully in the effect of a KRAS-GTL-C-OF inhibitor or at least augment the effect and aggregate resistance is potentially greater in non-slip cell lung cancer. Secondly, we know the objective response rate to single-agent cetaracid is a little bit higher, and that actually, oddly enough, if you're comparing, makes it easier to detect a difference if you're dealing with other versus a single. So I think that's a very good reason. Thirdly, we wanted to focus our attention on the single disease and make sure we got the right answer. But it absolutely doesn't say anything negative about the potential for 4630 and colon cancer. And I think there's every expectation that at some point in the future we will be doing that combination as well.

And if I could add to that, Eric, The Cochrane 101C study continues, and it is an exploratory study looking at multiple histotypes, so we're going to continue to get information out of that. I'd also highlight that in the formal part of the presentation, we did show an example of a colorectal cancer's tumor line that was relatively unresponsive or had low response to RMC6291 alone, but when combined with the shift inhibitor, actually developed quite deep regressions. tumor approach and start delving down one at a time. And the first approval for the McGrath, of course, is in lung cancer. So if we're looking for a place where we can make a difference and build on an improved treatment regimen, that would be the place to start. But by no means, as Steve said, are we excluding other opportunities.

Okay. Okay, great. And with respect to the Rason portfolio, it looks like you're deciding between two targets and naming a third development candidate between G12D and G13C. Just kind of curious to get a sense of your thinking that remains in deciding between sort of which you nominate here. And I guess how far apart are these compounds, I guess, in their preclinical development? Should we be thinking about multiple development candidates coming to the fore being named over the next year or so?

Yeah. I wouldn't read too much into that. That's the question of sort of the complex strategic decision about which one to move forward. have a bunch of teams competing with each other to put forth the best package when they've got the package together. And when they've got a package, we'll look at it and consider whether to approve moving forward with it. So it's not as if we ask one team to slow down and another team to speed up. I mean, everybody's moving as fast as they can. We also didn't explicitly say that we'll be choosing between G12D or G13C for this decision. We just said those are two that we've disclosed that are in lead optimization and we expect to select. a next development candidate coming up. But, you know, in principle, there could be other options on the table, too. So I wouldn't read too much into the, you know, whatever comes out of that. And we'll move things forward as quickly as we can. If one gets named and the other one doesn't, at some point thereafter, not too far after the other one, I'm sure we'll get named. And these programs are moving along well, as are unnamed target programs. that are continuing to work their way through.

Okay. All right. All right. I'll try not to over-interpret, I guess, from the slides going forward. Thanks for taking the questions.

All right. Thank you. As there are no more questions in the queue, I will turn the call back over to Dr. Goldsmith for his closing remarks.

Thank you, Operator, and thank you to Our analysts who just participated in the Q&A and to everyone for participating today and for your continued support of Revolution Medicine.

Ladies and gentlemen, this concludes today's conference call. Thank you for your participation. You may now disconnect.